This study will look at whether an investigational drug, called TD-9855, works and how safe it is when taken over a longer period of time to treat symptomatic neurogenic orthostatic hypotension (snOH) in people with Parkinson’s disease (PD), multiple system atrophy (MSA), or pure autonomic failure (PAF). It will also look at the effects of TD-9855 on general well-being and whether it can improve symptoms of neurogenic OH (nOH)

• Register: EUCTR
• Last refreshed on: 6 December 2021
• Main ID: EUCTR2018-003941-41-BG
• Date of registration: 26/06/2019
• Prospective Registration: Yes
• Primary sponsor: Theravance Biopharma Ireland Limited
• Public title: This study will look at whether an investigational drug, called TD-9855, works and how safe it is when taken over a longer period of time to treat symptomatic neurogenic orthostatic hypotension (snOH) in people with Parkinson’s disease (PD), multiple system atrophy (MSA), or pure autonomic failure (PAF). It will also look at the effects of TD-9855 on general well-being and whether it can improve symptoms of neurogenic OH (nOH)
• Scientific title: A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of TD-9855 in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure - Redwood
• Date of first enrolment: 10/10/2019
• Target sample size: 258
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-003941-41
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: yes; Other trial design description: Randomized withdrawal study; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Bulgaria, Canada, Chile, Denmark, Estonia, France, Germany, Hungary, Israel, Italy, Mexico, New Zealand, Peru, Poland, Portugal, Russian Federation, Spain, Ukraine, United Kingdom, United States

Contacts

• Name: Brett Haumann
• Affiliation: Theravance Biopharma Ireland Limited

• Name: Brett Haumann
• Affiliation: Theravance Biopharma Ireland Limited

Key inclusion & exclusion criteria

Inclusion criteria:
Inclusion Criteria (For 0169 Completers Group):
101. Completion of 4 weeks of double blind treatment in Study 0169 (V6) and, in the opinion of the Investigator, could benefit from continued treatment with TD-9855. No minimum score of OHSA#1 is required to enter V1 of Study 0170.
102. The subject has a minimum of 80% study medication compliance in Study 0169.
103. The subject must be able to understand the nature of the study and must provide written informed consent prior to the conduct of any study procedures (including an understanding that entry to Study 0170 may result in changes occurring in the subject’s current therapeutic regimen).
104. The subject must be willing to continue on treatment regardless of the possibility of randomization to either TD-9855 or PBO during the randomized withdrawal phase and must continue to meet the inclusion criteria for the preceding study (Study 0169) with the exception that tilt-table test, ESC review and approval of eligibility are not required for entry into Study 0170.

Inclusion Criteria (For De Novo Group):
1. Subject is male or female and at least 30 years old.
2. If subject is female, the subject must be non-pregnant and non-lactating. A woman of childbearing potential, must have a documented negative pregnancy test at screening.
NOTE: A woman is considered to be of childbearing potential unless she is postmenopausal (amenorrheic for at least 2 years) or documented to be surgically sterile (bilateral tubal ligation or total hysterectomy). A female subject may be admitted to the study on the basis of a negative urine pregnancy test. If the urine beta human chorionic gonadotropin (bHCG) test is positive, a serum bHCG test must be performed. The pregnancy test must be confirmed negative for a subject to be eligible for this study.
3. During the study and for 30 days after receiving the last dose of the study drug, females of childbearing potential or males capable of fathering children must agree to use highly effective birth control measures (failure rate <1% when used consistently and correctly) or agree to abstain from sexual intercourse.
4. Subject must meet the diagnostic criteria of nOH, as demonstrated by a sustained reduction in BP of =20 mmHg (systolic) or =10 mmHg (diastolic) within 3 min of being tilted-up =60 degrees from a supine position as determined by a tilt-table test.
5. Subject must score at least a 4 on the OHSA#1 at V1.
6. For subjects with PD only: Subject has a diagnosis of PD according to the United Kingdom Parkinson’s Disease Society (UKPDS) Brain Bank Criteria (1992).
7. For subjects with MSA only: Subject has a diagnosis of possible or probable MSA of the Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) according to The Gilman Criteria (2008).
8. For subjects with PAF only: Subject has documented impaired autonomic reflexes, including the Valsalva maneuver performed within 24 months from the date of randomization.
9. Subject has plasma NE levels = 100 pg/mL after being in seated position for 30 minutes.
10. Subject is willing and able to provide signed and dated written informed consent to participate prior to initiation of any study related procedures.
11. Subject is able to communicate well with the Investigator and understand clinic staff, understands the expectations of the study and is able to comply with the study procedures, requirements, and restrictions.

Are the trial subjects under 18? no
Number of subjects for this age range
Exclusion criteria:
Exclusion Criteria (For 0169 Completers Group):
1. Subject may not be enrolled in another clinical trial (other than exiting Study 0169).
2. Subject has psychiatric, neurological, or behavioral disorders that may interfere with the ability of subjects to give informed consent, or interfere with the conduct of the study.
3. Medical, laboratory, or surgical issues deemed by the Investigator to be clinically significant.
4. Uncooperative attitude or reasonable likelihood of non-compliance with the protocol.
5. Subject has a concurrent disease or condition that, in the opinion of the Investigator, would confound or interfere with study participation or evaluation of safety, tolerability, or pharmacokinetics of the study drug. Please refer to the protocol for additional exclusion criteria.
Exclusion Criteria (For De Novo Group):
1. neuropathy, including, but not limited to, amyloidosis and autoimmune
neuropathies. Subject has diabetes mellitus and diagnosis of PAF.
Subject with diabetes mellitus and either MSA or PD, will be evaluated
on a case by case basis by the medical monitor and considered ineligible
unless they meet all of the following criteria:
a. Well controlled type-2 DM in treatment with only oral medications and
diet
b. HgbA1C of =7.5% performed during screening or up to 12 weeks
before screening
c. No clinically evident peripheral neuropathy (e.g., normal sensory
examination on peripheral extremities)
d. No known retinopathy (e.g., annual ophthalmic exam is sufficient)
e. No nephropathy (e.g., absence of albuminuria and GFR >60).
2. Subject has a known intolerance to other NRIs or serotonin norepinephrine reuptake inhibitors (SNRIs).
3. Subject currently uses concomitant antihypertensive medication for the treatment of essential hypertension.
4. Subject has used strong CYP1A2 inhibitors or inducers within 7 days or 5 half-lives, whichever is longer, prior to V1 or requires concomitant use until the follow-up visit.
5. Subject has changed dose, frequency, or type of prescribed medication for orthostatic hypotension within 7 days prior to V1.
• Midodrine and droxidopa (if applicable) must be tapered off at least 7 days prior to V1.
6. Subject has known or suspected alcohol or substance abuse within the past 12 months
(Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR®] definition of alcohol or substance abuse).
7. Subject has a clinically unstable coronary artery disease, or has had a major cardiovascular or neurological event in the past 6 months.
8. Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to V1.
9. Subject has a history of untreated closed angle glaucoma, or treated closed angle glaucoma that, in the opinion of an ophthalmologist, might result in an increased risk to the subject.
10. Subject has any significant uncontrolled cardiac arrhythmia.
11. Subject has a Montreal Cognitive Assessment (MoCA) =23.
12. Subject is unable or unwilling to complete all protocol specified procedures including questionnaires.
13. Subject had a myocardial infarction in the past 6 months or has current unstable angina.
14. Subject has known congestive heart failure (New York Heart Association [NYHA]
Class 3 or 4).
15. Subject has had any malignant disease, other than carcinoma in situ of the cervix or basal cell carcinoma, within the past 2 years prior to screening.
16. Subject has a known gastrointestinal (GI) condition,

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Code: TD-9855
Pharmaceutical Form: Tablet
INN or Proposed INN: ampreloxetine hydrochloride
CAS Number: 1227056-84-9
Current Sponsor code: TD-9855
Other descriptive name: TD-9855
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: To evaluate the durability of effect of TD-9855 in subjects with symptomatic neurogenic orthostatic hypotension (symptomatic nOH) due to multiple system atrophy (MSA), Parkinson’s disease (PD), or pure autonomic failure (PAF) compared with placebo (PBO) over a double-blind, randomized withdrawal period of 6 weeks following an open label (OL) treatment of 16 weeks.

To evaluate the safety and tolerability of TD-9855 when taken for up to 22 weeks.

Primary end point(s): The primary study endpoint is the proportion of treatment failure at Week 6 during the double-blind randomized withdrawal phase. Treatment failure is defined as subjects who meet the following criteria at Week 6 following randomization (V9, D155):

Change (worsening) from baseline in OHSA#1 score of 1.0 point and worsening of disease severity as assessed by a 1 point change in PGI-S.

Secondary Objective: To evaluate the durability of effect of TD-9855 by symptom and activity assessments using Orthostatic Hypotension Symptom Assessment (OHSA) and Orthostatic Hypotension Daily Activity Scale (OHDAS).
To evaluate subject's symptomatic improvement as measured by a wearable device.

Timepoint(s) of evaluation of this end point: Week 6 following randomization (Visit 9, Day 155)

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Week 6 post randomization (Visit 9, Day 155)

Secondary end point(s): • Change from baseline in OHSA#1 at Week 6 post randomization (V9, D155)
• Change from baseline in OHSA composite score at Week 6 post randomization (V9, D155)
• Change from baseline in OHDAS composite score at Week 6 post randomization (V9, D155)
• Change from baseline in PGI-S at Week 6 post randomization (V9, D155)
• Change from baseline in percent of time spent in standing position as measured by a wearable device at Week 6 post randomization (V9, D155)
• Change from baseline in average number of steps taken as measured by a wearable device at Week 6 post randomization (V9, D155)

Additional secondary endpoints by disease type include:
For subjects with PD
• Change from baseline in UPDRS at Week 6 post randomization (V9, D155)
• Change from baseline in PDQ-8 at Week 6 post randomization (V9, D155)

For subjects with MSA
• Change from baseline in UMSARS at Week 6 post randomization (V9, D155)
• Change from baseline in COMPASS-31 at Week 6 post randomization (V9, D155)
Other efficacy endpoints are:
• Change from baseline in OHQ overall composite score at Week 6 post randomization (V9, D155)
• Change from baseline in EQ-5D-5L at Week 6 post randomization (V9, D155)
• NMSS at Week 6 post randomization (V9, D155)
• HADS at Week 6 post randomization (V9, D155)
• BSFC-s at Week 6 post randomization (V9, D155)

Secondary ID(s)

0170

2018-003941-41-GB

Source(s) of Monetary Support

Theravance Biopharma Ireland Limited

Ethics review

Status: Approved
Approval date: 10/10/2019
Contact: